Epigenetic alterations marked/mediated by promoter methylation and chromatin modificafions contribute to neoplastic phenotypes (disease pathogenesis, progression, resistance to therapy) by stably affecting the expression of crifical genes and pathways. In CML, preliminary data suggest an important contribution of epigenetic processes marked by promoter DNA methylafion in the progression of disease, as well as resistance to tyrosine kinase inhibitors (TKIs). Epigenetic processes may also affect immunity against CML neoplastic cells, for example by masking tumor anfigens. Based on this, we propose the following hypotheses: (i) Epigenefic processes (DNA methylation, histone code alterations) contribute to disease progression (CP to AP and BP) in CML, as well as to mutation-independent resistance to TKIs, by affecting the function of crifical pathways through stable modulation of gene expression, (ii) Targefing epigenefic silencing by DNA methylafion inhibitors and histone modifying drugs will complement TKI therapy in advanced CML. To address these hypotheses, we propose the following specific aims: (1) Global analysis of the CML epigenome. Using Methylated CpG Island (MCA) and Chromatin Immunoprecipitation coupled with deep sequencing (on the Solexa platform), we will determine common epigenefic abnormalities in CML cells (compared to normal CD34+ cells) at various phases (CP, AP, BP) and after resistance to TKIs develop. We will validate selected loci using standard technology and gene expression analysis, and use a pathway approach to studying funcfional epigenetic anomalies in CML. In addifion to unsupervised approaches to pathway identificafion, we will also examine specifically the PISK pathway (an interaction with project 4) and the JAhC/STAT pathway (an interaction with project 5) and potential immunomodulators such as tumor anfigens (in an interaction with project 2). (2) Predicfive and prognostic tesfing of selected epigenefic marks in prospecfive cohorts. In preliminary data, we have Identified a potential DNA methylation signature of progression in CML, as well as TKI resistance. In this aim, we will test the prognosfic/predicfive value of this gene panel in prospecfive cohorts of patients with early chronic phase CML enrolled on clinical trials of TKI (an interaction with project 1), as well as trials of stem cell transplantation for TKI resistant CML at all phases (an interaction with project 2). In subsequent years, genes/pathways idenfified in aim 1 will be tested in the same cohorts to potenfially improve on the predicfive power of these markers. (3) Pharmacodynamic analysis of epigenefic parameters in patients treated with epigenetic acting drugs. In this specific aim, we will analyze samples from patients enrolled on a clinical trial ofthe hypomethylating agent decitabine in combinafion with the TKI dasatinib (collaborafion with project 1), and a clinical trial of azacitidine to sfimulate anfi-CML immunity (project 2). We will correlate epigenetic patterns at baseline with likelihood of response, as well as epigenetic modulation (i.e. pharmacodynamic measurement) with likelihood of response to the drug/stem cell transplant intervention. This project will provide definitive and global data on epigenetic alterations in CML, pathways affected, prognostic significance as well as integration of epigenetic acting drugs in the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA049639-22
Application #
8380196
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
22
Fiscal Year
2012
Total Cost
$208,260
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Jain, Preetesh; Kantarjian, Hagop; Jain, Nitin et al. (2017) Clinical characteristics and outcomes of previously untreated patients with adult onset T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma with hyper-CVAD based regimens. Am J Hematol 92:E595-E597

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